Staging Parkinson's Disease Combining Motor and Nonmotor Symptoms Correlates with Disability and Quality of Life

Introduction In a degenerative disorder such as Parkinson's disease (PD), it is important to establish clinical stages that allow to know the course of the disease. Our aim was to analyze whether a scale combining Hoehn and Yahr's motor stage (H&Y) and the nonmotor symptoms burden (NMSB) (assessed by the nonmotor symptoms scale (NMSS)) provides information about the disability and the patient's quality of life (QoL) with regard to a defined clinical stage. Materials and Methods Cross-sectional study in which 603 PD patients from the COPPADIS cohort were classified according to H&Y (1, stage I; 2, stage II; 3, stage III; 4, stage IV/V) and NMSB (A: NMSS = 0–20; B: NMSS = 21–40; C: NMSS = 41–70; D: NMSS ≥ 71) in 16 stages (HY.NMSB, from 1A to 4D). QoL was assessed with the PDQ-39SI, PQ-10, and EUROHIS-QOL8 and disability with the Schwab&England ADL (Activities of Daily Living) scale. Results A worse QoL and greater disability were observed at a higher stage of H&Y and NMSB (p < 0.0001). Combining both (HY.NMSB), patients in stages 1C and 1D and 2C and 2D had significantly worse QoL and/or less autonomy for ADL than those in stages 2A and 2B and 3A and 3B, respectively (p < 0.005; e.g., PDQ-39SI in 1D [n = 15] vs 2A [n = 101]: 28.6 ± 17.1 vs 7.9 ± 5.8; p < 0.0001). Conclusion The HY.NMSB scale is simple and reflects the degree of patient involvement more accurately than the H&Y. Patients with a lower H&Y stage may be more affected if they have a greater NMS burden.


Introduction
Parkinson's disease (PD) is a progressive neurodegenerative disorder causing motor and nonmotor symptoms (NMS) that result in disability, loss of patient autonomy, and caregiver burden [1]. In a degenerative disease, it is important to establish clinical stages that allow the determination of disease progression for a patient based on different specific symptoms. Ideally, this clinical graduation should be simple to carry out so that it can be used universally in clinical practice. In the case of PD, and based on the classic motor symptoms of the disease, the Hoehn and Yahr (H&Y) scale is used to describe the progression of PD [2]. e scale was originally described in 1967 and included stages 1 through 5. It has since been modified with the addition of stages 1.5 and 2.5 to help describe the intermediate course of the disease [3]. is rating system has been largely supplemented by, firstly, the Unified Parkinson's Disease Rating Scale (UPDRS) [4], and more recently, the MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) [5], which assess limitation of Activities of Daily Living (ADL) and NMS. However, evaluating the patient using the UPDRS and/or MDS-UPDRS takes time; specialization is required and, importantly, do not allow the patient to be classified into a clearly differentiated stage, and several NMS are not included. Validated tools for assessing NMS such as the NMSQuest [6] and the nonmotor symptoms scale (NMSS) [7] are used both in trials and in clinical practice. Furthermore, it has been demonstrated that NMS are an important determinant and deteriorating factor of the quality of life (QoL) of PD patients [8,9]. Not only motor symptoms but also NMS increase in their severity and burden over time, increasing patients' disability, with additional worsening of their QoL, as well as caregivers' burden and consequential consumption of social resources by increasing societal costs.
at is why for staging PD it would be necessary to combine a motor with a nonmotor scale, which would allow the patient to be classified into stages considering both the degree of motor and nonmotor involvement.
Recently, it has been suggested that gradation of PD according to the motor impairment and burden of NMS is an unmet need for an appropriate management of patients [10]. Ray Chaudhuri et al. proposed a PD classification by H&Y staging and NMS burden level and demonstrated a correlation of both H&Y staging and NMS burden to disability and QoL [11]. However, QoL and autonomy for ADL regarding the stage considering both together, motor and nonmotor stages, were not analyzed. e H&Y scale provides quick information about the patient's condition, but since it does not include NMS, it is not very sensitive to reflect the real impact of that condition. Our hypothesis is 2 Parkinson's Disease that a patient with a lower H&Y stage but a greater NMS burden may present a worse QoL and greater disability than another patient with a more advanced H&Y stage but a lower NMS burden, so it would be beneficial to combine both aspects on a scale. e aim of this study was to classify PD patients from the COPPADIS cohort [12,13], regarding H&Y and NMS burden combined in a specific scale (HY.NMSB), and to compare QoL and autonomy for ADL between patients in a different HY.NMSB stages.

Materials and Methods
PD patients recruited from 35 centers of Spain from the COPPADIS cohort [13] from January 2016 to November 2017 were included in the study. Methodology about COPPADIS-2015 study can be consulted in https://bmcneurol. biomedcentral.com/articles/10.1186/s12883-016-0548-9. is is a multicenter, observational, longitudinal-prospective, 5-year follow-up study designed to analyze disease progression in a Spanish population of PD patients. e data for the present study (cross-sectional study) were obtained from the baseline evaluation. All patients included were diagnosed according to UK PD Brain Bank criteria. Exclusion criteria were as follows: non-PD parkinsonism, dementia (Mini Mental State Examination (MMSE) < 26), age <18 or >75 years, inability to read or understand the questionnaires, to be receiving any advanced therapy (continuous infusion of levodopa or apomorphine and/or with deep brain stimulation), and the presence of comorbidity, sequelae, or any disorder that could interfere with the assessment.
ere are 39 items grouped into 8 domains: (1) mobility (items 1 to 10); (2) Activities of Daily Living (items 11 to 16); (3) emotional well-being (items 17 to 22); (4) stigma (items 23 to 26); (5) social support (items 27 to 29); (6) cognition (items 30 to 33); (7) communication (items 34 to 36); and (8) pain and discomfort (items 37 to 39). For each item, the score may range from 0 (never) to 4 (always). e symptoms refer to the 4 weeks prior to assessment. Domain total scores are expressed as a percentage of the corresponding maximum possible score, and a Summary Index is obtained as average of the domain scores. e EUROHIS-QOL8 is an 8item global QoL questionnaire (quality of life, health status, energy, autonomy for Activities of Daily Living, self-esteem, social relationships, economic capacity, and habitat) derived from the WHOQOL-BREF. For each item, the score ranges from 0 (not at all) to 5 (completely). e total score is expressed as the mean of the individual scores. A higher score indicates a better QoL. e Schwab and England Activities of Daily Living Scale (ADLS) was used for assessing disability [17]. Functional dependency was defined as an ADLS score less than 80% (80% � completely independent; 70% � not completely independent) [18].

Results
A total of 603 PD patients (62.7 ± 8.9 years old; 59.5% males) from the COPPADIS cohort were included in the analysis. e mean disease duration was 5.7 ± 4.5 years. One-hundred and twenty-eight (22.9%) patients were in stage I of H&Y, 407 (67.5%) in stage II of H&Y, 49 (8.1%) in stage III of H&Y, and only 9 (1.5%) in stage IV/V of H&Y. e mean NMSS total score was 46.7 ± 38.2, presenting 162 (26.9%) patients with mild NMS burden, 174 (28.8%) with moderate NMS burden, 140 (23.2%) with severe NMS burden, and 127 (21.1%) with very severe NMS burden. No patient presented absence of nonmotor symptoms (NMSS � 0). Data about PD-related variables are shown in Table SM 1. When H&Y and NMS burden were combined (HY.NMSB), a higher percentage of patients with severe or very severe NMS burden in advanced H&Y stages (III and/or IV/V) (p < 0.0001) was observed ( Figure 1).

Discussion
e present study observed that the use in PD patients of a scale that combines the H&Y stage with the NMSS (HY.NMSB) could be useful since it would not only inform about motor and nonmotor aspects but would also serve to know how is the patient's QoL and autonomy for ADL. is is relevant because many PD patients can be in stages I to III of H&Y for many years and stratification regarding NMS burden providing useful information not only for diagnosis but also for monitoring the outcome and ideally the response to a medication.
Ray Chaudhuri et al. [11] proposed a new strategy for clinical classification of PD patients using the NMSS in 5 stratified levels of burden (0 � no NMS; 1 � NMSS, 1-20; 2 � NMSS, 21-40; 3 � NMSS, 41-70; 4 � NMSS > 70) and suggested that this simple assessment could be added to existing motor-based staging (i.e., H & Y) to complement PD assessment and avoid overlooking the weight of the NMS. In 951 PD patients, these authors observed a significant influence of NMS burden on disability and QoL, highlighting the need to include an NMS evaluation for a complete assessment of PD patients. We observed the same in 603 PD patients from the COPPADIS cohort. However, here, we define specifically a scale (HY.NMSB) combining the H&Y stage with the NMS burden: firstly, a number for the H&Y from 1 (stage I) to 4 (stage IV/V); secondly, a letter for the NMS burden from A (non NMS or mild NMS burden; NMSS 0-20) to D (very severe burden; NMSS > 70). Combining the number with the letter, a total of 16 stages are defined, from HY.NMSB 1A (H&Y I and non-NMS/mild NMS burden) to 4D (H&Y IV/V and very severe NMS burden). PD patients without NMS (i.e., NMSS total score � 0) are rare (none in this cohort), but in any case, they are included as "A" because there is really no difference between, for example, a patient with NMSS total score � 0 and another one with NMSS total score � 1 or 3. So, "A" is defined as a patient without NMS or mild NMS burden. On the other hand and with the idea of simplifying the scale,      PD, but this qualification cannot be supported attending the load of NMS and any domain/s they belong. e NMS present in PD may be very variable in number and type, and they maintain only a moderate association with the motor disturbances [10,11,19,20]. In fact, although as expected, patients with mild NMS burden (A; 39.8%) were the most frequent in the group with a stage I of H&Y and patients with very severe NMS burden (D; 44.4%) in the group with H&Y IV/V; more than 30% of the patients in stage I of H&Y had severe or very severe NMS burden. Clinical and        [21], and it seems necessary in daily practice to know the frequency and the severity of NMS in PD patients, even in early PD patients, because NMS burden could be significant, and this one impacts on their QoL and contributes to disability [7,9,15,22]. Very recently, two PD subtypes have been suggested [23,24], and it would be of great interest to know if very early PD patients with very severe NMS burden could correspond with the body-first (bottom-up) type and those with mild NMS burden with the brain-first (top-down) type. e application of the HY.NMSB scale could have different uses: (1) a fast and relatively simple way of knowing the motor and nonmotor states of a PD patient, stratifying him/ her into a group (diagnosis value; first visit); (2) to monitor the long-term evolution of the patient (prognosis value; follow-up visits); (3) to monitor the response of a patient to a specific therapeutic intervention. In fact, the NMSS total score has been considered as the primary efficacy variable in recent trials [25], and it is known that some NMS can be improved, with dopaminergic medication or nondopaminergic medication [26]. In this context, the HY.NMSB could be used for defining a specific population or as an outcome parameter in clinical trials. For example, nabilone has very recently demonstrated to improve NMS in PD patients in a phase 2 trial [27], being an interesting possibility to identify what patients changed from a superior stage of the HY.NMSB to an inferior stage (e.g., from 2C to 2 B). Finally, the HY-NMSB scale could be useful to indirectly estimate the patient's perception of QoL and disability. e correlation of H&Y, NMSS, and NMS burden with QoL and disability has been frequently reported [7][8][9]22], including in PD patients from the COPPADIS cohort [15,18], but this is the first time that the relationship considering both motor stage (H&Y) and NMS burden (NMSS) at the same time has been analyzed, and it is important because the influence of NMS burden on QoL perception is critical. An inherent limitation of the proposed classification (HY.NMSB) is the fact that the classification according to NMS is carried out taking into account the total NMS burden but without considering what exactly these symptoms are. Importantly, some NMS could help clinical practitioners to identify patients who are at different stages of the disease, such as hallucinations, fainting, inability to control body sphincters, or believing in unlikely facts [28]. Moreover, and compared with the International Parkinson and Movement Disorder Society─Nonmotor Rating Scale (MDS-NMS) [29], the NMSS collects the patient's perception about different NMS in the previous 4 weeks but does not about nonmotor fluctuations.
A very important limitation is that our sample is not fully representative of the PD population due to inclusion and exclusion criteria (i.e., age limit, no dementia, no severe comorbidities, and no second line therapies) which subsequently entails a bias toward early PD. e majority of the patients from this cohort were in the stage I or II of the H&Y (90.4%), so the same analysis with the proposed classification should be carried out in a cohort with more patients in advanced stages of H&Y. In spite of this and importantly, during the first 5 to 10 years of the disease, many patients with PD will be in stage II of the H&Y, and introducing the NMS burden will help to differentiate the degree of nonmotor affectation, that importantly correlates with QoL perception. In other words, the results of the present study are applicable for a long time to the majority of PD patients, especially in early young PD patients. Second, all scales or questionnaires used for assessing motor and NMS are validated except PQ-10 [8,15]. ird, NMS were recorded with the NMSS, but specifically, as we commented nonmotor fluctuations were not identified [30]. Fourth, the OFF state (12 hours without taking medication) was considered for defining the H&Y stage because it represents a more natural state of the disease less conditioned by the symptomatic effect of the medication. Moreover, in PD patients with motor fluctuations, the symptoms during the OFF state mostly impact on QoL and autonomy. In any case, previously, similar results applying the HY.NMSB were observed when the H&Y stage was defined during the ON state in 149 PD patients from the CASINO cohort [8,31]. In the COPPADIS cohort, the results were similar as well when the H&Y was defined during the ON state in those PD patients with motor fluctuations (data not shown). Fifth, the time it took to administer the HY.BMSB scale was not calculated. Finally, this is a cross-sectional study, but the aim of the COPPADIS-2015 study [12] is to follow-up the cohort for 5 years, so changes in HY.NMSB and the relationship with changes in other variables could be analyzed.
In conclusion, this is the first time that a specific scale combing the H&Y stage and the NMSS (HY.NMSB scale) is applied in PD patients for knowing the relationship with the patient's QoL perception and disability regarding the stage. e HY.NMSB scale is simple and reflects the degree of patient involvement more accurately than the H&Y. Patients with a lower H&Y stage may be more affected if they have a greater NMS burden. ese results need to be replicated in a larger and well-distributed cohort of patients by motor stage. Data Availability e protocol and the statistical analysis plan are available on request. Deidentified participants data are not available for legal and ethical reasons.

Conflicts of Interest
Santos García D has received honoraria for educational presentations and advice service by AbbVie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, Italfarmaco, and Teva. Paz González JM has received honoraria for educational presentations and/or advice service by UCB Pharma, Lundbeck, KRKA, and Zambon. Jesús S has received honoraria from AbbVie, Bial, Merz, UCB, and Zambon and holds the competitive contract "Juan Rodés" supported by the Instituto de Salud Carlos III. She has received grants from the Spanish Ministry of Economy and Competitiveness (PI18/ 01898) and the Consejería de Salud de la Junta de Andalucía (PI-0459-2018). Aguilar M obtained from UCB and Schwabe with assistance to a Congress and Nutricia with assistance to a Congress and payment of lecture. Planellas LL has received travel bursaries grant from AbbVie. García Caldentey J has received honoraria for educational presentations and advice service by Qualigen, Nutricia, AbbVie, Italfarmaco, UCB Pharma, Lundbeck, Zambon, Bial and Teva. Caballol N has received honoraria from Bial, Italfarmaco, Qualigen, Zambon, UCB, Teva, and KRKA and sponsorship from Zambon, TEVA, and AbbVie for attending medical conferences. Legarda I has received honoraria for educational presentations and advice service by AbbVie, UCB Pharma, Zambon, Bial, and Teva. Hernández Vara J has received travel bursaries and educational grants from AbbVie and has received honoraria for educational presentations from